Article | Published:

Zizimin1, a novel Cdc42 activator, reveals a new GEF domain for Rho proteins

Nature Cell Biology volume 4, pages 639647 (2002) | Download Citation

Subjects

Abstract

The Rho family GTPases Rac, Rho and Cdc42 are critical in regulating the actin-based cytoskeleton, cell migration, growth, survival and gene expression. These GTPases are activated by guanine nucleotide-exchange factors (GEFs). A biochemical search for Cdc42 activators led to the cloning of zizimin1, a new protein whose overexpression induces Cdc42 activation. Sequence comparison combined with mutational analysis identified a new domain, which we named CZH2, that mediates direct interaction with Cdc42. CZH2-containing proteins constitute a new superfamily that includes the so-called 'CDM' proteins that bind to and activate Rac. Together, the results suggest that CZH2 is a new GEF domain for the Rho family of proteins.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Accessions

References

  1. 1.

    & Rho GTPases and their effector proteins. Biochem. J. 348, 241–255 (2000).

  2. 2.

    Effectors for the Rho GTPases. Curr. Opin. Cell Biol. 11, 95–102 (1999).

  3. 3.

    & GEFs: structural basis for their activation of small GTP-binding proteins. Trends Biochem. Sci. 24, 306–311 (1999).

  4. 4.

    & The Dbl family of oncogenes. Curr. Opin. Cell Biol. 8, 216–222 (1996).

  5. 5.

    et al. Cellular transformation and guanine nucleotide exchange activity are catalyzed by a common domain on the dbl oncogene product. J. Biol. Chem. 269, 62–65 (1994).

  6. 6.

    & C. elegans phagocytosis and cell-migration protein CED-5 is similar to human DOCK180. Nature 392, 501–504 (1998).

  7. 7.

    et al. Activation of Rac1 by a Crk SH3-binding protein, DOCK180. Genes Dev. 12, 3331–3336 (1998).

  8. 8.

    et al. Non-adherent cell-specific expression of DOCK2, a member of the human CDM-family proteins. Biochim. Biophys. Acta 1452, 179–187 (1999).

  9. 9.

    , , , & Evidence that DOCK180 upregulates signals from the CrkII-p130(Cas) complex. J. Biol. Chem. 273, 24479–24484 (1998).

  10. 10.

    et al. Haematopoietic cell-specific CDM family protein DOCK2 is essential for lymphocyte migration. Nature 412, 826–831 (2001).

  11. 11.

    & CED-2/CrkII and CED-10/Rac control phagocytosis and cell migration in Caenorhabditis elegans. Nature Cell Biol. 2, 131–136 (2000).

  12. 12.

    et al. Myoblast city, the Drosophila homolog of DOCK180/CED-5, is required in a Rac signaling pathway utilized for multiple developmental processes. Genes Dev. 12, 3337–3342 (1998).

  13. 13.

    et al. Identification of a novel guanine nucleotide exchange factor for the Rho GTPase. J. Biol. Chem. 271, 25452–25458 (1996).

  14. 14.

    , , , & Adhesion to the extracellular matrix regulates the coupling of the small GTPase Rac to its effector PAK. EMBO J. 19, 2008–2014 (2000).

  15. 15.

    , , & IpaC induces actin polymerization and filopodia formation during Shigella entry into epithelial cells. EMBO J. 18, 3249–3262 (1999).

  16. 16.

    et al. The Pfam protein families database. Nucleic Acids Res. 28, 263–266 (2000).

  17. 17.

    et al. Predicting coiled coils by use of pairwise residue correlations. Proc. Natl Acad. Sci. USA 92, 8259–8263 (1995).

  18. 18.

    Prediction and analysis of coiled-coil structures. Methods Enzymol. 266, 513–525 (1996).

  19. 19.

    Rho guanine dissociation inhibitors: pivotal molecules in cellular signalling. Cell Signal. 11, 545–554 (1999).

  20. 20.

    et al. A modulator of the Rho family G proteins, RhoGDI, binds these G proteins via an immunoglobulin-like domain and a flexible N-terminal arm. Structure 5, 623–633 (1997).

  21. 21.

    , , , & S. typhimurium encodes an activator of Rho GTPases that induces membrane ruffling and nuclear responses in host cells. Cell 93, 815–826 (1998).

  22. 22.

    et al. Biochemical analysis of SopE from Salmonella typhimurium, a highly efficient guanosine nucleotide exchange factor for RhoGTPases. J. Biol. Chem. 274, 30501–30509 (1999).

  23. 23.

    et al. Ced-12/elmo, a novel member of the crkII/dock180/rac pathway, is required for phagocytosis and cell migration. Cell 107, 27–41 (2001).

  24. 24.

    , & Plant GTPases: the Rhos in bloom. Trends Cell. Biol. 10, 141–146 (2000).

  25. 25.

    et al. Dbl and Vav mediate transformation via mitogen-activated protein kinase pathways that are distinct from those activated by oncogenic Ras. Mol. Cell. Biol. 14, 6848–6857 (1994).

  26. 26.

    , , , & A role for p21-activated kinase in endothelial cell migration. J. Cell Biol. 147, 831–844 (1999).

  27. 27.

    et al. Prediction of the coding sequences of unidentified human genes. XIV. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 6, 197–205 (1999).

  28. 28.

    , , , & Rho GTPases control migration and polarization of adhesion molecules and cytoskeletal ERM components in T lymphocytes. Eur. J. Immunol. 29, 3609–3620 (1999).

  29. 29.

    Multiple sequence alignment with hierarchical clustering. Nucleic Acids Res. 16, 10881–10890 (1988).

Download references

Acknowledgements

We thank T. Nagase from the Kazusa DNA Research Institute for providing the KIAA1058 cDNA. We thank C. Der for providing Dbl expressing NIH-3T3 cells and R. Cerione for the D118A Cdc42. We are grateful to J. Han for advice about GEF assays and to N. Alderson for excellent technical assistance. This work was supported by grants from the U.S. Public Health Service (RO1 GM41721) to M.A.S., grants from the American Heart Association to N.M. and W.B.K. and from the Leukemia & Lymphoma society to M.A.P.

Author information

Affiliations

  1. Division of Vascular Biology, Department of Cell Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla CA 92037, USA

    • Nahum Meller
    • , Mohammad Irani-Tehrani
    • , William B. Kiosses
    • , Miguel A. Del Pozo
    •  & Martin A. Schwartz

Authors

  1. Search for Nahum Meller in:

  2. Search for Mohammad Irani-Tehrani in:

  3. Search for William B. Kiosses in:

  4. Search for Miguel A. Del Pozo in:

  5. Search for Martin A. Schwartz in:

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Martin A. Schwartz.

Supplementary information

PDF files

  1. 1.

    Supplementary figure

    Figure S1. Gel analysis of immunoprecipitates.

About this article

Publication history

Received

Revised

Accepted

Published

DOI

https://doi.org/10.1038/ncb835

Further reading